Modulation of Therapeutic ResponseIn the interest of improving cancer treatment, considerable attention has been placed on the modification of radiation damage. The major goal of this project is to define and understand those aspects of tumor physiology, including cellular and molecular processes that ultimately define the very nature of a tumor such that a particular dose of ionizing radiation, when used will be more effective. We have recently shown that radiation-induced gene expression profiles differ significantly for cells exposed in vitro versus the same cells growing as a solid tumor in vivo further underscoring the influence of the tumor microenvironment on the radiation response. The interaction of a variety of chemotherapy and/or molecularly targeted agents with radiation is under study to determine if tumors can be made more sensitive or normal tissues more resistant to radiation treatment. Research continues with halofuginone, an inhibitor of TGF beta signaling pathway, which exhibits cytotoxicity and radiosensitization to a variety of different types of human tumor cell lines and protects against radiation-induced late effects in normal tissues in vivo. Importantly we have shown that halofuginone can protect against radiation-induced soft tissue fibrosis even when administered two weeks post-irradiation. Additional agents that block the TGF beta-signaling pathway are being evaluated with the goal of identifying and implementing agents that will provide selective radioprotection of normal tissues with perhaps sensitization of tumor. Another major goal of this project is to develop functional imaging techniques to better characterize factors important in the tumor microenvironment and normal tissues that may prevent or diminish agents from impacting radiation response. It is well established that hypoxia is a major determinant of radiation sensitivity and that many human tumors are hypoxic. Therefore, we are using several murine tumor models to study tumor hypoxia. Our approach is to use current invasive techniques and extend that information to non-invasive methods that are under development, such that patient tumor treatment profiles may optimized on an individual basis. We have demonstrated that placement of lithium phthalocyanine crystals in tissue provides an accurate means of assessing tissue oxygen levels by electron paramagnetic resonance (EPR). Using novel EPR equipment developed in the Radiation Biology Branch we have recently shown that non-invasive tissue oxygen concentration can be evaluated in mice using a specific redox probe contrast agent. Three-dimensional oxygen images can be acquired in less than 3 minutes with oxygen resolution to 0.5 mm. Our EPR non-invasive functional imaging approaches should enhance our ability to better understand the tumor microenvironment and develop strategies to effectively attack potential barriers that currently limit the effectiveness of cancer treatment modalities.